We have developed rodent models of prenatal nicotine exposure that simulate the plasma levels found in smokers or in users of the transdermal nicotine patch, and have demonstrated that nicotine itself is a neuroteratogen that elicits synaptic functional changes appearing after an extended period of apparent normality. These effects target catecholamine systems and we have preliminary data indicating involvement of 5HT systems as well. Brain development continues into adolescence, the period in which nearly all smokers begin smoking, and we have developed a comparable rodent model of adolescent nicotine administration; again, catecholamine systems are targeted and we have preliminary data for 5HT. It is clear that a subset of smokers are using tobacco to self-medicate for depression; additionally, adolescent smoking is associated with higher incidence of subsequent depression. These findings lead to the current hypothesis: namely that nicotine, during a critical period of brain development, alters the set-point for 5HT activity, at the level of presynaptic function, at receptor signal transduction cascades, or both. This will be pursued in fetal and adolescent nicotine exposure models, utilizing neurochemical, cell signaling, and behavioral approaches. Aim 1. To determine how prenatal nicotine exposure alters 5HT synaptic function and behaviors known to be targeted in models of 5HT dysfunction. Evaluate development of 5HT projections, using nerve terminal markers, 5HT turnover, and the ability of acute nicotine challenge to release 5HT; studies conducted from birth to adulthood. 5HT signal transduction assessed with receptor ligand binding and linkages to adenylyl cyclase. Aim 2. To determine whether the critical period for nicotine- induced alterations in the programming of 5HT function extends into adolescence. We will assess 5HT synaptic function and behaviors during adolescent nicotine treatment and withdrawal, using the same endpoints as studied with the prenatal nicotine model. Aim 3. To determine whether prenatal nicotine exposure alters the response to subsequent adolescent nicotine administration. Animals exposed prenatally to nicotine will receive adolescent nicotine treatment and the response of 5HT systems and behavior will be assessed, along with catecholaminergic responses and nicotinic receptors known to be affected by adolescent nicotine.